{"gene":"CD96","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"CD96 (TACTILE) promotes NK cell adhesion to target cells by directly interacting with the poliovirus receptor (CD155/PVR), and this interaction stimulates cytotoxicity of activated NK cells and mediates acquisition of PVR from target cells.","method":"Cell adhesion assays, cytotoxicity assays, flow cytometry with NK cells and PVR-expressing target cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct functional assays (adhesion, cytotoxicity, ligand acquisition) in a single focused study with clear mechanistic readouts","pmids":["15034010"],"is_preprint":false},{"year":2007,"finding":"Murine CD96 binds both CD155 and nectin-1 as adhesion ligands, and CD96/CD155 interaction mediates T cell adhesion to CD155-expressing cells; CD96 is expressed on T cells and NK cells in a pattern closely resembling human CD96.","method":"Monoclonal antibody blocking assays, T cell adhesion assays to insect cells expressing CD155, flow cytometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal blocking with multiple antibody clones plus cell adhesion functional readout, single lab","pmids":["17971293"],"is_preprint":false},{"year":2008,"finding":"CD96 interaction with CD155 is mediated via the outermost V-like first Ig domain; human CD96 exists in two splice variants (variant 1 with I-like and variant 2 with V-like second domain), and variant 2 predominates. A trigonocephaly-associated missense mutation (T280M) in the third domain of CD96 significantly decreases binding of both variants to CD155, suggesting the downstream Ig domains allosterically modulate the binding site.","method":"Chimeric human/murine CD96 receptor binding assays, splice variant characterization, mutational analysis of patient-derived missense mutation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with chimeric receptors plus mutagenesis plus splice variant functional characterization, multiple orthogonal methods in one study","pmids":["19056733"],"is_preprint":false},{"year":2014,"finding":"CD96 competes with CD226 (DNAM-1) for binding to CD155, and CD96 limits NK cell function by direct inhibition. Cd96-deficient mice exhibit hyperinflammatory responses to LPS and resistance to experimental lung metastases, placing CD96 as a negative regulator of NK cell cytokine responses.","method":"Cd96 knockout mice, competitive binding assays for CD155, LPS challenge model, experimental metastasis models, cytokine measurement","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple in vivo phenotypic readouts plus competitive binding assay, replicated across multiple experimental systems","pmids":["24658051"],"is_preprint":false},{"year":2007,"finding":"Mutations in CD96 (TACTILE) cause a form of the C (Opitz trigonocephaly) syndrome; cells expressing the patient-derived T280M mutant CD96 lost adhesion and growth activities in vitro, indicating that CD96-driven cell adhesion is critical for developmental processes.","method":"Chromosomal translocation mapping, missense mutation identification in patients, in vitro cell adhesion and growth assays with mutant CD96","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro assay with patient-derived mutation plus human genetic evidence, single lab","pmids":["17847009"],"is_preprint":false},{"year":2007,"finding":"CD96 is expressed on the majority of CD34+CD38- AML leukemic stem cells (LSC) but not on normal hematopoietic stem cells; CD96+ AML cells are enriched for LSC activity as demonstrated by preferential engraftment in xenograft recipients.","method":"FACS sorting of CD96+ vs CD96- AML fractions, xenotransplantation into irradiated Rag2-/-γc-/- mice, engraftment analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — prospective fractionation followed by in vivo engraftment functional assay, multiple patient samples tested","pmids":["17576927"],"is_preprint":false},{"year":2018,"finding":"The crystal structure of CD96 first Ig domain (D1) bound to necl-5 (CD155) ectodomain revealed that CD96 recognizes CD155 D1 via a conserved 'lock-and-key' interaction, with specificity for CD155 over nectin-2 conferred by a novel 'ancillary key' structural motif within CD96 D1. Mutational analysis confirmed this residue is critical for CD155 binding.","method":"X-ray crystallography of CD96-D1:CD155 complex, binding assays, site-directed mutagenesis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis validation, rigorous mechanistic characterization of binding interface","pmids":["30528596"],"is_preprint":false},{"year":2019,"finding":"Human CD96 directly interacts with nectin-1 in vitro; the binding site for CD96 is located on the nectin-1 V-domain at a canonical nectin adhesion interface. The affinity of nectin-1 for CD96 is lower than for CD155. Overexpression of nectin-1 on K562 cells increased their susceptibility to NK-92 cell cytotoxicity.","method":"In vitro binding assays, affinity measurements, K562 cell overexpression of nectin-1-GFP with NK cytotoxicity assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assay with affinity quantification plus functional cytotoxicity assay, single lab","pmids":["30759143"],"is_preprint":false},{"year":2019,"finding":"CD96 functions as an immune checkpoint on CD8+ T cells, and blocking CD96 suppresses primary tumor growth in a CD8+ T cell-dependent manner. CD96-deficient CD8+ T cells promote greater tumor control than CD96-sufficient CD8+ T cells; anti-CD96 combined with anti-PD-1 increases IFNγ-expressing CD8+ T cells.","method":"Cd96-deficient mouse tumor models, CD8+ T cell depletion experiments, flow cytometry, combination checkpoint blockade experiments","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus antibody blockade with multiple tumor models and cell-depletion controls establishing CD8+ T cell dependence","pmids":["30894377"],"is_preprint":false},{"year":2020,"finding":"CD96 has co-stimulatory function on CD8+ T cells: crosslinking CD96 on human or mouse CD8+ T cells induces activation, effector cytokine production, and proliferation via MEK-ERK signaling. CD96 increases frequencies of NUR77- and T-bet-expressing CD8+ T cells and enhances cytotoxic effector activity. Antibody blockade or genetic ablation of CD96 on CD8+ T cells impaired transcription factor and cytokine expression in vivo.","method":"CD96 crosslinking assays on human and mouse CD8+ T cells, MEK-ERK pathway inhibition, CD96 knockout, in vivo models, flow cytometry","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (crosslinking, pathway inhibition, genetic KO, in vivo models) in a single study establishing co-stimulatory mechanism","pmids":["32043568"],"is_preprint":false},{"year":2018,"finding":"CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells: CD96low Th9 cells produce more IL-9 and cause severe intestinal inflammation and skin graft rejection upon transfer into Rag1-deficient mice, whereas CD96high Th9 cells show reduced expansion and no colitis. Blockade of CD96 completely restored expansion and inflammatory properties of CD96high Th9 cells, indicating an inhibitory role for CD96 co-signaling in Th9 cells.","method":"Single-cell transcription profiling, adoptive transfer of CD96low vs CD96high Th9 cells into Rag1-/- mice, anti-CD96 blockade, flow cytometry","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic cell-transfer experiments with functional inflammatory readout plus antibody blockade rescue, multiple orthogonal methods","pmids":["29531070"],"is_preprint":false},{"year":2018,"finding":"Anti-CD96 antibodies that block CD96-CD155 interactions (mAbs 3.3 and 6A6) bind the first Ig domain of mouse CD96; a non-blocking antibody (8B10) binds the second Ig domain. Anti-metastatic activity of blocking mAbs was lost in CD155-deficient mice but retained in CD226-deficient mice is dependent on NK cells and IFNγ; all anti-CD96 clones lost activity in CD226-deficient mice, placing CD226 as required for CD96-mediated NK anti-metastatic activity.","method":"Domain-mapping of antibody binding by flow cytometry, multiple experimental metastasis models, CD155-KO and CD226-KO mice, NK depletion, IFNγ neutralization","journal":"Oncoimmunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic knockout models with multiple metastasis models and mechanistic dissection of ligand-dependency, single lab but rigorous epistasis","pmids":["29721390"],"is_preprint":false},{"year":2022,"finding":"Tumor cell-intrinsic CD96 enhances mitochondrial fatty acid β-oxidation via the CD155-CD96-Src-Stat3-Opa1 signaling pathway, promoting chemoresistance in breast cancer stem cells. In vivo inhibition of cancer cell-intrinsic CD96 enhances chemotherapeutic response in patient-derived xenograft models.","method":"CD96 inhibition in cancer cell lines and patient-derived xenografts, pathway analysis (Src, Stat3, Opa1), mitochondrial fatty acid β-oxidation assays, in vivo chemotherapy response","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo PDX model plus pathway mechanistic dissection, single lab","pmids":["36581470"],"is_preprint":false},{"year":2023,"finding":"Patients with giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint: macrophages retain CD155 in the endoplasmic reticulum and fail to surface-display it. CD155-low antigen-presenting cells expand CD4+CD96+ T cells that become tissue-invasive and release IL-9, which drives vessel wall destruction in a humanized mouse model.","method":"Patient macrophage studies, humanized mouse model of GCA, anti-IL-9 antibody treatment, recombinant IL-9 administration, flow cytometry","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — humanized mouse model with functional intervention (anti-IL-9, rIL-9) plus patient tissue analysis, single lab","pmids":["37075705"],"is_preprint":false},{"year":1998,"finding":"The TH-111 antibody (assigned to CD96 cluster) immunoprecipitated the TACTILE (CD96) antigen and found it associated with the transferrin receptor on leukemic cells; CD96 (TACTILE) was identified as a marker of T-cell ALL and a subset of immature AML.","method":"Immunoprecipitation, antibody-based immunophenotyping by flow cytometry","journal":"Experimental hematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunoprecipitation experiment showing association with transferrin receptor, minimal mechanistic follow-up","pmids":["9845376"],"is_preprint":false}],"current_model":"CD96 (TACTILE) is an immunoglobulin superfamily transmembrane receptor expressed on T cells and NK cells that binds CD155 (PVR/necl-5) via its first Ig domain and also interacts with nectin-1; it competes with the activating receptor CD226 for shared ligands and can function as either an inhibitory checkpoint (suppressing NK cell cytokine responses and Th9 inflammatory activity) or a co-stimulatory receptor (enhancing CD8+ T cell activation via MEK-ERK signaling) depending on cell context; within tumor cells it drives chemoresistance via a CD155-CD96-Src-Stat3-Opa1 pathway promoting mitochondrial fatty acid β-oxidation; CD96 mutations that reduce CD155 binding cause the C (Opitz trigonocephaly) syndrome, and loss of CD96 surface checkpoint function contributes to autoimmune vasculitis by permitting pathogenic Th9 expansion."},"narrative":{"mechanistic_narrative":"CD96 (TACTILE) is an immunoglobulin-superfamily transmembrane receptor on T cells and NK cells that engages nectin-family adhesion ligands to tune immune effector responses [PMID:15034010, PMID:24658051]. It binds the poliovirus receptor CD155 (necl-5) through its outermost V-like first Ig domain, with the crystal structure of the CD96 D1:CD155 complex revealing a conserved lock-and-key interface whose CD155-versus-nectin-2 specificity is set by an 'ancillary key' motif [PMID:19056733, PMID:30528596]; CD96 also binds nectin-1 at a lower affinity via the canonical nectin V-domain interface [PMID:30759143]. This adhesive engagement was first defined functionally by CD96-dependent NK adhesion to CD155-bearing targets and acquisition of CD155 from those cells [PMID:15034010]. CD96 competes with the activating receptor CD226 (DNAM-1) for CD155, and through this competition acts as a negative regulator of NK-cell cytokine output, with Cd96-deficient mice showing hyperinflammatory LPS responses and resistance to experimental metastasis [PMID:24658051, PMID:29721390]. The receptor's output is context-dependent: it serves as an inhibitory checkpoint on CD8+ T cells, where blockade enhances CD8-dependent tumor control and synergizes with anti-PD-1 [PMID:30894377], yet crosslinking CD96 also drives co-stimulatory CD8+ T-cell activation, cytokine production, and proliferation through MEK-ERK signaling [PMID:32043568]. In Th9 cells, CD96 expression restrains IL-9 production and inflammatory expansion, and a defective CD155-CD96 checkpoint—macrophages retaining CD155 in the ER—permits expansion of pathogenic CD96+ IL-9-producing T cells in giant cell arteritis [PMID:29531070, PMID:37075705]. Beyond immune cells, tumor-intrinsic CD96 drives chemoresistance via a CD155-CD96-Src-Stat3-Opa1 axis promoting mitochondrial fatty acid β-oxidation [PMID:36581470], and CD96 marks AML leukemic stem cells with engraftment activity [PMID:17576927]. A T280M missense mutation in the third Ig domain that reduces CD155 binding causes a form of C (Opitz trigonocephaly) syndrome, linking CD96-mediated adhesion to development [PMID:19056733, PMID:17847009].","teleology":[{"year":1998,"claim":"Before any ligand or function was known, CD96/TACTILE needed to be defined as a discrete leukocyte antigen and clinical marker, establishing the protein and its disease associations.","evidence":"Immunoprecipitation and antibody immunophenotyping on leukemic cells","pmids":["9845376"],"confidence":"Low","gaps":["Single immunoprecipitation with minimal mechanistic follow-up","Functional significance of transferrin receptor association not established","No ligand identified"]},{"year":2004,"claim":"The central question of what CD96 does was first answered by identifying CD155/PVR as its ligand and showing the interaction supports NK adhesion and cytotoxicity, establishing CD96 as a functional adhesion receptor.","evidence":"Cell adhesion, cytotoxicity, and ligand-acquisition assays with NK cells and PVR+ targets","pmids":["15034010"],"confidence":"High","gaps":["Did not resolve which Ig domain mediates binding","Signaling output downstream of CD96 unknown","Inhibitory vs activating role not distinguished"]},{"year":2007,"claim":"Ligand specificity was broadened and the receptor framed in a developmental context by showing nectin-1 is a second adhesion ligand and that CD96 mutations cause C syndrome.","evidence":"Antibody-blocking adhesion assays in mouse plus translocation mapping and patient mutation functional assays","pmids":["17971293","17847009"],"confidence":"Medium","gaps":["Mechanism linking adhesion defect to trigonocephaly developmental phenotype unresolved","Single-lab functional assays for patient mutation","Relative contribution of CD155 vs nectin-1 in development not separated"]},{"year":2008,"claim":"The molecular basis of binding was localized to the V-like D1 domain and the disease mutation explained, showing the C-syndrome T280M mutation in D3 allosterically reduces CD155 binding of both splice variants.","evidence":"Chimeric human/murine receptor binding assays, splice variant characterization, mutagenesis of patient mutation","pmids":["19056733"],"confidence":"High","gaps":["Atomic-resolution interface not yet defined","Mechanism of allosteric modulation by downstream domains not structurally explained"]},{"year":2014,"claim":"The functional valence was resolved in NK cells by demonstrating CD96 competes with activating CD226 for CD155 and acts as an inhibitory checkpoint, with knockout mice showing enhanced anti-metastatic immunity.","evidence":"Cd96 knockout mice, competitive CD155 binding assays, LPS and experimental metastasis models","pmids":["24658051"],"confidence":"High","gaps":["Intracellular signaling motifs mediating inhibition not mapped","Whether the same logic applies to T cells unaddressed"]},{"year":2018,"claim":"The receptor's role was extended to adaptive immunity and the ligand-dependency of therapeutic blockade dissected, showing CD96 restrains Th9 IL-9 inflammatory potential and that anti-CD96 anti-metastatic activity requires CD155 and CD226.","evidence":"Adoptive transfer of CD96low/high Th9 cells into Rag1-/- mice, antibody domain-mapping, CD155-KO and CD226-KO metastasis models","pmids":["29531070","29721390"],"confidence":"High","gaps":["Signaling pathway connecting CD96 to IL-9 suppression unknown","How CD226 is required for CD96-blockade efficacy mechanistically unresolved"]},{"year":2018,"claim":"The CD96:CD155 interface was solved at atomic resolution, defining a lock-and-key binding mode and an 'ancillary key' motif conferring CD155 over nectin-2 specificity.","evidence":"X-ray crystallography of CD96-D1:CD155 complex with mutagenesis validation","pmids":["30528596"],"confidence":"High","gaps":["Structure of full-length receptor or signaling-competent complex not determined","Does not address nectin-1 binding geometry"]},{"year":2019,"claim":"CD96's bifunctional immune role and its second ligand interface were clarified, establishing CD96 as a CD8+ T-cell checkpoint whose blockade boosts tumor control and defining the nectin-1 binding site.","evidence":"Cd96-deficient tumor models with CD8 depletion and anti-PD-1 combination; in vitro nectin-1 binding/affinity and NK cytotoxicity assays","pmids":["30894377","30759143"],"confidence":"Medium","gaps":["Functional role of CD96-nectin-1 binding in vivo unclear","Reciprocal validation of nectin-1 interaction limited to single lab"]},{"year":2020,"claim":"An apparent paradox was addressed by showing CD96 can also co-stimulate CD8+ T cells through MEK-ERK signaling, revealing context-dependent dual activity rather than purely inhibitory function.","evidence":"CD96 crosslinking on human and mouse CD8+ T cells, MEK-ERK inhibition, genetic KO and in vivo models","pmids":["32043568"],"confidence":"High","gaps":["What determines inhibitory vs co-stimulatory outcome not defined","Direct link between ligand engagement and MEK-ERK activation not structurally explained"]},{"year":2022,"claim":"A tumor-cell-intrinsic role was uncovered, showing CD96 drives chemoresistance through a CD155-CD96-Src-Stat3-Opa1 axis promoting mitochondrial fatty acid β-oxidation.","evidence":"CD96 inhibition in cell lines and PDX models, pathway analysis, β-oxidation assays, in vivo chemotherapy response","pmids":["36581470"],"confidence":"Medium","gaps":["Single-lab pathway dissection","How a surface receptor couples to mitochondrial metabolism mechanistically incomplete"]},{"year":2023,"claim":"The checkpoint logic was placed in human autoimmune disease, showing defective CD155 surface display creates a failed CD155-CD96 checkpoint that expands pathogenic IL-9-producing CD96+ T cells in giant cell arteritis.","evidence":"Patient macrophage studies, humanized GCA mouse model with anti-IL-9 and recombinant IL-9 interventions","pmids":["37075705"],"confidence":"Medium","gaps":["Why macrophages retain CD155 in the ER not explained","Single-lab humanized model"]},{"year":null,"claim":"The molecular switch governing whether CD96 acts as an inhibitory checkpoint or co-stimulatory receptor, and the intracellular signaling motifs coupling ligand engagement to each outcome, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined cytoplasmic signaling motif map","Determinants of context-dependent valence unknown","Integration of CD96/CD226 competition with downstream signaling unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,6,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,8,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8,9,10]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["CD155","CD226","NECTIN1","TFRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P40200","full_name":"T-cell surface protein tactile","aliases":["Cell surface antigen CD96","T cell-activated increased late expression protein"],"length_aa":585,"mass_kda":65.6,"function":"May be involved in adhesive interactions of activated T and NK cells during the late phase of the immune response. Promotes NK cell-target adhesion by interacting with PVR present on target cells. May function at a time after T and NK cells have penetrated the endothelium using integrins and selectins, when they are actively engaging diseased cells and moving within areas of inflammation","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P40200/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD96","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD96","total_profiled":1310},"omim":[{"mim_id":"612859","title":"T-CELL IMMUNORECEPTOR WITH IMMUNOGLOBULIN AND ITIM DOMAINS; TIGIT","url":"https://www.omim.org/entry/612859"},{"mim_id":"606037","title":"CD96 ANTIGEN; CD96","url":"https://www.omim.org/entry/606037"},{"mim_id":"605039","title":"BOHRING-OPITZ SYNDROME; BOPS","url":"https://www.omim.org/entry/605039"},{"mim_id":"211750","title":"C SYNDROME","url":"https://www.omim.org/entry/211750"},{"mim_id":"173850","title":"POLIOVIRUS RECEPTOR; PVR","url":"https://www.omim.org/entry/173850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":57.5}],"url":"https://www.proteinatlas.org/search/CD96"},"hgnc":{"alias_symbol":["TACTILE"],"prev_symbol":[]},"alphafold":{"accession":"P40200","domains":[{"cath_id":"2.60.40.10","chopping":"30-137","consensus_level":"high","plddt":82.6684,"start":30,"end":137},{"cath_id":"2.60.40.10","chopping":"145-267","consensus_level":"high","plddt":72.1618,"start":145,"end":267},{"cath_id":"2.60.40.10","chopping":"274-378","consensus_level":"high","plddt":81.5414,"start":274,"end":378}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P40200","model_url":"https://alphafold.ebi.ac.uk/files/AF-P40200-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P40200-F1-predicted_aligned_error_v6.png","plddt_mean":64.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD96","jax_strain_url":"https://www.jax.org/strain/search?query=CD96"},"sequence":{"accession":"P40200","fasta_url":"https://rest.uniprot.org/uniprotkb/P40200.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P40200/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P40200"}},"corpus_meta":[{"pmid":"12917686","id":"PMC_12917686","title":"P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12917686","citation_count":1240,"is_preprint":false},{"pmid":"24658051","id":"PMC_24658051","title":"The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions.","date":"2014","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24658051","citation_count":392,"is_preprint":false},{"pmid":"28258695","id":"PMC_28258695","title":"TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy.","date":"2017","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/28258695","citation_count":378,"is_preprint":false},{"pmid":"10430952","id":"PMC_10430952","title":"Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10430952","citation_count":339,"is_preprint":false},{"pmid":"17576927","id":"PMC_17576927","title":"CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17576927","citation_count":311,"is_preprint":false},{"pmid":"15034010","id":"PMC_15034010","title":"Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155).","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15034010","citation_count":291,"is_preprint":false},{"pmid":"27293187","id":"PMC_27293187","title":"Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27293187","citation_count":288,"is_preprint":false},{"pmid":"24746027","id":"PMC_24746027","title":"Merkel cells transduce and encode tactile stimuli to drive Aβ-afferent impulses.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/24746027","citation_count":244,"is_preprint":false},{"pmid":"11835980","id":"PMC_11835980","title":"Tactile, acoustic and vestibular systems sum to elicit the startle reflex.","date":"2002","source":"Neuroscience and biobehavioral reviews","url":"https://pubmed.ncbi.nlm.nih.gov/11835980","citation_count":232,"is_preprint":false},{"pmid":"30209395","id":"PMC_30209395","title":"Touch and tactile neuropathic pain sensitivity are set by corticospinal projections.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30209395","citation_count":207,"is_preprint":false},{"pmid":"27620276","id":"PMC_27620276","title":"Molecular Pathways: Targeting CD96 and TIGIT for Cancer Immunotherapy.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27620276","citation_count":192,"is_preprint":false},{"pmid":"31398341","id":"PMC_31398341","title":"Targeting Peripheral Somatosensory Neurons to Improve Tactile-Related Phenotypes in ASD Models.","date":"2019","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/31398341","citation_count":191,"is_preprint":false},{"pmid":"28652360","id":"PMC_28652360","title":"Simulating tactile signals from the whole hand with millisecond precision.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28652360","citation_count":148,"is_preprint":false},{"pmid":"25174006","id":"PMC_25174006","title":"Edge-orientation processing in first-order tactile neurons.","date":"2014","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25174006","citation_count":117,"is_preprint":false},{"pmid":"35045339","id":"PMC_35045339","title":"Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions.","date":"2022","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/35045339","citation_count":104,"is_preprint":false},{"pmid":"30894377","id":"PMC_30894377","title":"CD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function.","date":"2019","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/30894377","citation_count":98,"is_preprint":false},{"pmid":"25209272","id":"PMC_25209272","title":"Anxiety- and depression-like behavior and impaired neurogenesis evoked by peripheral neuropathy persist following resolution of prolonged tactile hypersensitivity.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25209272","citation_count":88,"is_preprint":false},{"pmid":"32043568","id":"PMC_32043568","title":"CD96 functions as a co-stimulatory receptor to enhance CD8+ T cell activation and effector responses.","date":"2020","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32043568","citation_count":81,"is_preprint":false},{"pmid":"10465458","id":"PMC_10465458","title":"Regulation of galanin and neuropeptide Y in dorsal root ganglia and dorsal horn in rat mononeuropathic models: possible relation to tactile hypersensitivity.","date":"1999","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10465458","citation_count":80,"is_preprint":false},{"pmid":"17971293","id":"PMC_17971293","title":"The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17971293","citation_count":79,"is_preprint":false},{"pmid":"21193025","id":"PMC_21193025","title":"CXCR4 signaling mediates morphine-induced tactile hyperalgesia.","date":"2010","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21193025","citation_count":79,"is_preprint":false},{"pmid":"32488078","id":"PMC_32488078","title":"A flexible artificial intrinsic-synaptic tactile sensory organ.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32488078","citation_count":79,"is_preprint":false},{"pmid":"17346886","id":"PMC_17346886","title":"Oral and spinal melatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors.","date":"2007","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/17346886","citation_count":79,"is_preprint":false},{"pmid":"9080460","id":"PMC_9080460","title":"Adenosine receptor activation suppresses tactile hypersensitivity and potentiates spinal cord stimulation in mononeuropathic rats.","date":"1997","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/9080460","citation_count":67,"is_preprint":false},{"pmid":"1710971","id":"PMC_1710971","title":"Modification of cortical somatosensory evoked potentials during tactile exploration and simple active and passive movements.","date":"1991","source":"Electroencephalography and clinical neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/1710971","citation_count":67,"is_preprint":false},{"pmid":"18363823","id":"PMC_18363823","title":"Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury.","date":"2008","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18363823","citation_count":65,"is_preprint":false},{"pmid":"19056733","id":"PMC_19056733","title":"CD96 interaction with CD155 via its first Ig-like domain is modulated by alternative splicing or mutations in distal Ig-like domains.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19056733","citation_count":64,"is_preprint":false},{"pmid":"34688712","id":"PMC_34688712","title":"Specialized Mechanosensory Epithelial Cells in Mouse Gut Intrinsic Tactile Sensitivity.","date":"2021","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/34688712","citation_count":63,"is_preprint":false},{"pmid":"33224630","id":"PMC_33224630","title":"TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer.","date":"2020","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/33224630","citation_count":62,"is_preprint":false},{"pmid":"17920585","id":"PMC_17920585","title":"Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats.","date":"2007","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17920585","citation_count":62,"is_preprint":false},{"pmid":"592198","id":"PMC_592198","title":"Human tactile detection thresholds: modification by inputs from specific tactile receptor classes.","date":"1977","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/592198","citation_count":61,"is_preprint":false},{"pmid":"19378878","id":"PMC_19378878","title":"Tactile spatial working memory activates the dorsal extrastriate cortical pathway in congenitally blind individuals.","date":"2008","source":"Archives italiennes de biologie","url":"https://pubmed.ncbi.nlm.nih.gov/19378878","citation_count":60,"is_preprint":false},{"pmid":"27626490","id":"PMC_27626490","title":"Altered expression of CD226 and CD96 on natural killer cells in patients with pancreatic cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27626490","citation_count":57,"is_preprint":false},{"pmid":"35288463","id":"PMC_35288463","title":"Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer.","date":"2022","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35288463","citation_count":56,"is_preprint":false},{"pmid":"16207882","id":"PMC_16207882","title":"Activin induces tactile allodynia and increases calcitonin gene-related peptide after peripheral inflammation.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16207882","citation_count":55,"is_preprint":false},{"pmid":"15363879","id":"PMC_15363879","title":"Development of tactile allodynia and thermal hyperalgesia by intrathecally administered platelet-activating factor in mice.","date":"2004","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/15363879","citation_count":52,"is_preprint":false},{"pmid":"30528596","id":"PMC_30528596","title":"Structural Basis for CD96 Immune Receptor Recognition of Nectin-like Protein-5, CD155.","date":"2018","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/30528596","citation_count":46,"is_preprint":false},{"pmid":"31807945","id":"PMC_31807945","title":"Mechanisms of Tactile Sensory Phenotypes in Autism: Current Understanding and Future Directions for Research.","date":"2019","source":"Current psychiatry reports","url":"https://pubmed.ncbi.nlm.nih.gov/31807945","citation_count":45,"is_preprint":false},{"pmid":"20457848","id":"PMC_20457848","title":"Comparing tactile pattern and vibrotactile frequency discrimination: a human FMRI study.","date":"2010","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/20457848","citation_count":45,"is_preprint":false},{"pmid":"24902717","id":"PMC_24902717","title":"Controlling the activation of the Bv8/prokineticin system reduces neuroinflammation and abolishes thermal and tactile hyperalgesia in neuropathic animals.","date":"2014","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24902717","citation_count":45,"is_preprint":false},{"pmid":"33298247","id":"PMC_33298247","title":"Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy.","date":"2021","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/33298247","citation_count":44,"is_preprint":false},{"pmid":"29531070","id":"PMC_29531070","title":"CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29531070","citation_count":43,"is_preprint":false},{"pmid":"36581470","id":"PMC_36581470","title":"Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β-Oxidation.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36581470","citation_count":41,"is_preprint":false},{"pmid":"29109250","id":"PMC_29109250","title":"Molecular basis of tactile specialization in the duck bill.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29109250","citation_count":41,"is_preprint":false},{"pmid":"32612110","id":"PMC_32612110","title":"CD96, a new immune checkpoint, correlates with immune profile and clinical outcome of glioma.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32612110","citation_count":40,"is_preprint":false},{"pmid":"29721390","id":"PMC_29721390","title":"CD96 targeted antibodies need not block CD96-CD155 interactions to promote NK cell anti-metastatic activity.","date":"2018","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/29721390","citation_count":39,"is_preprint":false},{"pmid":"31074575","id":"PMC_31074575","title":"Tactile UV- and Solar-Light Multi-Sensing Rechargeable Batteries with Smart Self-Conditioned Charge and Discharge.","date":"2019","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/31074575","citation_count":37,"is_preprint":false},{"pmid":"9845376","id":"PMC_9845376","title":"Antibodies TC-12 (\"unique\") and TH-111 (CD96) characterize T-cell acute lymphoblastic leukemia and a subgroup of acute myeloid leukemia.","date":"1998","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/9845376","citation_count":37,"is_preprint":false},{"pmid":"21638686","id":"PMC_21638686","title":"Tactile teaching: Exploring protein structure/function using physical models*.","date":"2006","source":"Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular Biology","url":"https://pubmed.ncbi.nlm.nih.gov/21638686","citation_count":37,"is_preprint":false},{"pmid":"33247136","id":"PMC_33247136","title":"Tactile modulation of memory and anxiety requires dentate granule cells along the dorsoventral axis.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33247136","citation_count":35,"is_preprint":false},{"pmid":"23752100","id":"PMC_23752100","title":"Tactile interactions lead to coherent motion and enhanced chemotaxis of migrating cells.","date":"2013","source":"Physical biology","url":"https://pubmed.ncbi.nlm.nih.gov/23752100","citation_count":35,"is_preprint":false},{"pmid":"28123010","id":"PMC_28123010","title":"Optimal delineation of single C-tactile and C-nociceptive afferents in humans by latency slowing.","date":"2017","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/28123010","citation_count":35,"is_preprint":false},{"pmid":"30222899","id":"PMC_30222899","title":"The immune checkpoint CD96 defines a distinct lymphocyte phenotype and is highly expressed on tumor-infiltrating T cells.","date":"2018","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30222899","citation_count":34,"is_preprint":false},{"pmid":"32695752","id":"PMC_32695752","title":"Immune and Clinical Features of CD96 Expression in Glioma by in silico Analysis.","date":"2020","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32695752","citation_count":33,"is_preprint":false},{"pmid":"34417435","id":"PMC_34417435","title":"BCL9 regulates CD226 and CD96 checkpoints in CD8+ T cells to improve PD-1 response in cancer.","date":"2021","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34417435","citation_count":33,"is_preprint":false},{"pmid":"18633115","id":"PMC_18633115","title":"Sulfasalazine blocks the development of tactile allodynia in diabetic rats.","date":"2008","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18633115","citation_count":33,"is_preprint":false},{"pmid":"30759143","id":"PMC_30759143","title":"Interaction between nectin-1 and the human natural killer cell receptor CD96.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30759143","citation_count":32,"is_preprint":false},{"pmid":"32764229","id":"PMC_32764229","title":"Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32764229","citation_count":31,"is_preprint":false},{"pmid":"17847009","id":"PMC_17847009","title":"Mutations in CD96, a member of the immunoglobulin superfamily, cause a form of the C (Opitz trigonocephaly) syndrome.","date":"2007","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17847009","citation_count":31,"is_preprint":false},{"pmid":"26924961","id":"PMC_26924961","title":"Tactile Stimulation Evokes Long-Lasting Potentiation of Purkinje Cell Discharge In Vivo.","date":"2016","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26924961","citation_count":29,"is_preprint":false},{"pmid":"33027220","id":"PMC_33027220","title":"Different forms of traumatic brain injuries cause different tactile hypersensitivity profiles.","date":"2021","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/33027220","citation_count":29,"is_preprint":false},{"pmid":"29908482","id":"PMC_29908482","title":"Development of tactile sensory circuits in the CNS.","date":"2018","source":"Current opinion in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29908482","citation_count":28,"is_preprint":false},{"pmid":"17643411","id":"PMC_17643411","title":"Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat.","date":"2007","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17643411","citation_count":28,"is_preprint":false},{"pmid":"24648403","id":"PMC_24648403","title":"Tactile sensory system: encoding from the periphery to the cortex.","date":"2014","source":"Wiley interdisciplinary reviews. Systems biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24648403","citation_count":27,"is_preprint":false},{"pmid":"36674817","id":"PMC_36674817","title":"CD96 as a Potential Immune Regulator in Cancers.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674817","citation_count":26,"is_preprint":false},{"pmid":"24751333","id":"PMC_24751333","title":"Expression of CD90, CD96, CD117, and CD123 on different hematopoietic cell populations from pediatric patients with acute myeloid leukemia.","date":"2014","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/24751333","citation_count":26,"is_preprint":false},{"pmid":"29719247","id":"PMC_29719247","title":"A Corticothalamic Circuit for Refining Tactile Encoding.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29719247","citation_count":26,"is_preprint":false},{"pmid":"22879978","id":"PMC_22879978","title":"Enhanced ADCC activity of affinity maturated and Fc-engineered mini-antibodies directed against the AML stem cell antigen CD96.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22879978","citation_count":24,"is_preprint":false},{"pmid":"25491757","id":"PMC_25491757","title":"Peripheral alpha4beta2 nicotinic acetylcholine receptor signalling attenuates tactile allodynia and thermal hyperalgesia after nerve injury in mice.","date":"2014","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25491757","citation_count":24,"is_preprint":false},{"pmid":"28744900","id":"PMC_28744900","title":"Mechanical and tactile incompatibilities cause reproductive isolation between two young damselfly species.","date":"2017","source":"Evolution; international journal of organic evolution","url":"https://pubmed.ncbi.nlm.nih.gov/28744900","citation_count":24,"is_preprint":false},{"pmid":"19565229","id":"PMC_19565229","title":"Sensory information in perceptual-motor sequence learning: visual and/or tactile stimuli.","date":"2009","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/19565229","citation_count":24,"is_preprint":false},{"pmid":"37075705","id":"PMC_37075705","title":"Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis.","date":"2023","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37075705","citation_count":23,"is_preprint":false},{"pmid":"12356451","id":"PMC_12356451","title":"Synaptic transmission between single tactile and kinaesthetic sensory nerve fibers and their central target neurones.","date":"2002","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12356451","citation_count":22,"is_preprint":false},{"pmid":"37860691","id":"PMC_37860691","title":"Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37860691","citation_count":22,"is_preprint":false},{"pmid":"6470768","id":"PMC_6470768","title":"The receptor potential and adaptation in the cockroach tactile spine.","date":"1984","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/6470768","citation_count":22,"is_preprint":false},{"pmid":"26993794","id":"PMC_26993794","title":"Tactile stimulation effects on hippocampal neurogenesis and spatial learning and memory in prenatally stressed rats.","date":"2016","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/26993794","citation_count":22,"is_preprint":false},{"pmid":"24468216","id":"PMC_24468216","title":"Tactile stimulation and neonatal isolation affect behavior and oxidative status linked to cocaine administration in young rats.","date":"2014","source":"Behavioural processes","url":"https://pubmed.ncbi.nlm.nih.gov/24468216","citation_count":20,"is_preprint":false},{"pmid":"28391288","id":"PMC_28391288","title":"CD33, CD96 and Death Associated Protein Kinase (DAPK) Expression Are Associated with the Survival Rate and/or Response to the Chemotherapy in the Patients with Acute Myeloid Leukemia (AML).","date":"2017","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/28391288","citation_count":19,"is_preprint":false},{"pmid":"38359825","id":"PMC_38359825","title":"ASICs mediate fast excitatory synaptic transmission for tactile discrimination.","date":"2024","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/38359825","citation_count":19,"is_preprint":false},{"pmid":"25386856","id":"PMC_25386856","title":"Nogo receptor 1 limits tactile task performance independent of basal anatomical plasticity.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25386856","citation_count":19,"is_preprint":false},{"pmid":"24306439","id":"PMC_24306439","title":"Contralateral tactile masking between forearms.","date":"2013","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/24306439","citation_count":19,"is_preprint":false},{"pmid":"25671616","id":"PMC_25671616","title":"In vivo tactile stimulation-evoked responses in Caenorhabditis elegans amphid sheath glia.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25671616","citation_count":19,"is_preprint":false},{"pmid":"37025036","id":"PMC_37025036","title":"Bionic Tactile-Gustatory Receptor for Object Identification Based on All-Polymer Electrochemical Transistor.","date":"2023","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/37025036","citation_count":18,"is_preprint":false},{"pmid":"34776857","id":"PMC_34776857","title":"Sensory Adaptation in the Whisker-Mediated Tactile System: Physiology, Theory, and Function.","date":"2021","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34776857","citation_count":16,"is_preprint":false},{"pmid":"39994389","id":"PMC_39994389","title":"Electrochemiluminescent tactile visual synapse enabling in situ health monitoring.","date":"2025","source":"Nature materials","url":"https://pubmed.ncbi.nlm.nih.gov/39994389","citation_count":16,"is_preprint":false},{"pmid":"33826906","id":"PMC_33826906","title":"Spatial integration during active tactile sensation drives orientation perception.","date":"2021","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/33826906","citation_count":15,"is_preprint":false},{"pmid":"35233588","id":"PMC_35233588","title":"A bio-inspired tactile nociceptor constructed by integrating wearable sensing paper and a VO2 threshold switching memristor.","date":"2022","source":"Journal of materials chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/35233588","citation_count":15,"is_preprint":false},{"pmid":"23272144","id":"PMC_23272144","title":"Differential expression of CD96 surface molecule represents CD8⁺ T cells with dissimilar effector function during HIV-1 infection.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23272144","citation_count":14,"is_preprint":false},{"pmid":"35997524","id":"PMC_35997524","title":"Impact of intratumoural CD96 expression on clinical outcome and therapeutic benefit in gastric cancer.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/35997524","citation_count":13,"is_preprint":false},{"pmid":"36004818","id":"PMC_36004818","title":"Natural killer cell profiles in recurrent pregnancy loss: Increased expression and positive associations with TACTILE and LILRB1.","date":"2022","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/36004818","citation_count":13,"is_preprint":false},{"pmid":"31332000","id":"PMC_31332000","title":"Functional Architecture and Encoding of Tactile Sensorimotor Behavior in Rat Posterior Parietal Cortex.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31332000","citation_count":13,"is_preprint":false},{"pmid":"26642704","id":"PMC_26642704","title":"Expressions of CD96 and CD123 in Bone Marrow Cells of Patients with Myelodysplastic Syndromes.","date":"2015","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/26642704","citation_count":12,"is_preprint":false},{"pmid":"34122431","id":"PMC_34122431","title":"Loss of CD96 Expression as a Marker of HIV-Specific CD8+ T-Cell Differentiation and Dysfunction.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34122431","citation_count":12,"is_preprint":false},{"pmid":"32445638","id":"PMC_32445638","title":"Bidirectional pharmacological perturbations of the noradrenergic system differentially affect tactile detection.","date":"2020","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32445638","citation_count":12,"is_preprint":false},{"pmid":"29703788","id":"PMC_29703788","title":"Primary Tactile Thalamus Spiking Reflects Cognitive Signals.","date":"2018","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29703788","citation_count":12,"is_preprint":false},{"pmid":"25933968","id":"PMC_25933968","title":"Celecoxib reduces hyperalgesia and tactile allodynia in diabetic rats.","date":"2014","source":"Pharmacological reports : PR","url":"https://pubmed.ncbi.nlm.nih.gov/25933968","citation_count":12,"is_preprint":false},{"pmid":"37119137","id":"PMC_37119137","title":"High-fidelity encoding of mechanostimuli by tactile food-sensing neurons requires an ensemble of ion channels.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37119137","citation_count":12,"is_preprint":false},{"pmid":"30216497","id":"PMC_30216497","title":"Red nucleus interleukin-1β evokes tactile allodynia through activation of JAK/STAT3 and JNK signaling pathways.","date":"2018","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/30216497","citation_count":12,"is_preprint":false},{"pmid":"37689920","id":"PMC_37689920","title":"Characterization of the impact of chlorogenic acids on tactile perception in coffee through an inverse effect on mouthcoating sensation.","date":"2023","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/37689920","citation_count":12,"is_preprint":false},{"pmid":"32903627","id":"PMC_32903627","title":"Neonatal Tactile Stimulation Alters Behaviors in Heterozygous Serotonin Transporter Male Rats: Role of the Amygdala.","date":"2020","source":"Frontiers in behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32903627","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47558,"output_tokens":3776,"usd":0.099657,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11651,"output_tokens":3933,"usd":0.07829,"stage2_stop_reason":"end_turn"},"total_usd":0.177947,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CD96 (TACTILE) promotes NK cell adhesion to target cells by directly interacting with the poliovirus receptor (CD155/PVR), and this interaction stimulates cytotoxicity of activated NK cells and mediates acquisition of PVR from target cells.\",\n      \"method\": \"Cell adhesion assays, cytotoxicity assays, flow cytometry with NK cells and PVR-expressing target cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assays (adhesion, cytotoxicity, ligand acquisition) in a single focused study with clear mechanistic readouts\",\n      \"pmids\": [\"15034010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Murine CD96 binds both CD155 and nectin-1 as adhesion ligands, and CD96/CD155 interaction mediates T cell adhesion to CD155-expressing cells; CD96 is expressed on T cells and NK cells in a pattern closely resembling human CD96.\",\n      \"method\": \"Monoclonal antibody blocking assays, T cell adhesion assays to insect cells expressing CD155, flow cytometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal blocking with multiple antibody clones plus cell adhesion functional readout, single lab\",\n      \"pmids\": [\"17971293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD96 interaction with CD155 is mediated via the outermost V-like first Ig domain; human CD96 exists in two splice variants (variant 1 with I-like and variant 2 with V-like second domain), and variant 2 predominates. A trigonocephaly-associated missense mutation (T280M) in the third domain of CD96 significantly decreases binding of both variants to CD155, suggesting the downstream Ig domains allosterically modulate the binding site.\",\n      \"method\": \"Chimeric human/murine CD96 receptor binding assays, splice variant characterization, mutational analysis of patient-derived missense mutation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with chimeric receptors plus mutagenesis plus splice variant functional characterization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19056733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD96 competes with CD226 (DNAM-1) for binding to CD155, and CD96 limits NK cell function by direct inhibition. Cd96-deficient mice exhibit hyperinflammatory responses to LPS and resistance to experimental lung metastases, placing CD96 as a negative regulator of NK cell cytokine responses.\",\n      \"method\": \"Cd96 knockout mice, competitive binding assays for CD155, LPS challenge model, experimental metastasis models, cytokine measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple in vivo phenotypic readouts plus competitive binding assay, replicated across multiple experimental systems\",\n      \"pmids\": [\"24658051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mutations in CD96 (TACTILE) cause a form of the C (Opitz trigonocephaly) syndrome; cells expressing the patient-derived T280M mutant CD96 lost adhesion and growth activities in vitro, indicating that CD96-driven cell adhesion is critical for developmental processes.\",\n      \"method\": \"Chromosomal translocation mapping, missense mutation identification in patients, in vitro cell adhesion and growth assays with mutant CD96\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro assay with patient-derived mutation plus human genetic evidence, single lab\",\n      \"pmids\": [\"17847009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD96 is expressed on the majority of CD34+CD38- AML leukemic stem cells (LSC) but not on normal hematopoietic stem cells; CD96+ AML cells are enriched for LSC activity as demonstrated by preferential engraftment in xenograft recipients.\",\n      \"method\": \"FACS sorting of CD96+ vs CD96- AML fractions, xenotransplantation into irradiated Rag2-/-γc-/- mice, engraftment analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — prospective fractionation followed by in vivo engraftment functional assay, multiple patient samples tested\",\n      \"pmids\": [\"17576927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The crystal structure of CD96 first Ig domain (D1) bound to necl-5 (CD155) ectodomain revealed that CD96 recognizes CD155 D1 via a conserved 'lock-and-key' interaction, with specificity for CD155 over nectin-2 conferred by a novel 'ancillary key' structural motif within CD96 D1. Mutational analysis confirmed this residue is critical for CD155 binding.\",\n      \"method\": \"X-ray crystallography of CD96-D1:CD155 complex, binding assays, site-directed mutagenesis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis validation, rigorous mechanistic characterization of binding interface\",\n      \"pmids\": [\"30528596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human CD96 directly interacts with nectin-1 in vitro; the binding site for CD96 is located on the nectin-1 V-domain at a canonical nectin adhesion interface. The affinity of nectin-1 for CD96 is lower than for CD155. Overexpression of nectin-1 on K562 cells increased their susceptibility to NK-92 cell cytotoxicity.\",\n      \"method\": \"In vitro binding assays, affinity measurements, K562 cell overexpression of nectin-1-GFP with NK cytotoxicity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assay with affinity quantification plus functional cytotoxicity assay, single lab\",\n      \"pmids\": [\"30759143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD96 functions as an immune checkpoint on CD8+ T cells, and blocking CD96 suppresses primary tumor growth in a CD8+ T cell-dependent manner. CD96-deficient CD8+ T cells promote greater tumor control than CD96-sufficient CD8+ T cells; anti-CD96 combined with anti-PD-1 increases IFNγ-expressing CD8+ T cells.\",\n      \"method\": \"Cd96-deficient mouse tumor models, CD8+ T cell depletion experiments, flow cytometry, combination checkpoint blockade experiments\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus antibody blockade with multiple tumor models and cell-depletion controls establishing CD8+ T cell dependence\",\n      \"pmids\": [\"30894377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD96 has co-stimulatory function on CD8+ T cells: crosslinking CD96 on human or mouse CD8+ T cells induces activation, effector cytokine production, and proliferation via MEK-ERK signaling. CD96 increases frequencies of NUR77- and T-bet-expressing CD8+ T cells and enhances cytotoxic effector activity. Antibody blockade or genetic ablation of CD96 on CD8+ T cells impaired transcription factor and cytokine expression in vivo.\",\n      \"method\": \"CD96 crosslinking assays on human and mouse CD8+ T cells, MEK-ERK pathway inhibition, CD96 knockout, in vivo models, flow cytometry\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (crosslinking, pathway inhibition, genetic KO, in vivo models) in a single study establishing co-stimulatory mechanism\",\n      \"pmids\": [\"32043568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells: CD96low Th9 cells produce more IL-9 and cause severe intestinal inflammation and skin graft rejection upon transfer into Rag1-deficient mice, whereas CD96high Th9 cells show reduced expansion and no colitis. Blockade of CD96 completely restored expansion and inflammatory properties of CD96high Th9 cells, indicating an inhibitory role for CD96 co-signaling in Th9 cells.\",\n      \"method\": \"Single-cell transcription profiling, adoptive transfer of CD96low vs CD96high Th9 cells into Rag1-/- mice, anti-CD96 blockade, flow cytometry\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic cell-transfer experiments with functional inflammatory readout plus antibody blockade rescue, multiple orthogonal methods\",\n      \"pmids\": [\"29531070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Anti-CD96 antibodies that block CD96-CD155 interactions (mAbs 3.3 and 6A6) bind the first Ig domain of mouse CD96; a non-blocking antibody (8B10) binds the second Ig domain. Anti-metastatic activity of blocking mAbs was lost in CD155-deficient mice but retained in CD226-deficient mice is dependent on NK cells and IFNγ; all anti-CD96 clones lost activity in CD226-deficient mice, placing CD226 as required for CD96-mediated NK anti-metastatic activity.\",\n      \"method\": \"Domain-mapping of antibody binding by flow cytometry, multiple experimental metastasis models, CD155-KO and CD226-KO mice, NK depletion, IFNγ neutralization\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic knockout models with multiple metastasis models and mechanistic dissection of ligand-dependency, single lab but rigorous epistasis\",\n      \"pmids\": [\"29721390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tumor cell-intrinsic CD96 enhances mitochondrial fatty acid β-oxidation via the CD155-CD96-Src-Stat3-Opa1 signaling pathway, promoting chemoresistance in breast cancer stem cells. In vivo inhibition of cancer cell-intrinsic CD96 enhances chemotherapeutic response in patient-derived xenograft models.\",\n      \"method\": \"CD96 inhibition in cancer cell lines and patient-derived xenografts, pathway analysis (Src, Stat3, Opa1), mitochondrial fatty acid β-oxidation assays, in vivo chemotherapy response\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo PDX model plus pathway mechanistic dissection, single lab\",\n      \"pmids\": [\"36581470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Patients with giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint: macrophages retain CD155 in the endoplasmic reticulum and fail to surface-display it. CD155-low antigen-presenting cells expand CD4+CD96+ T cells that become tissue-invasive and release IL-9, which drives vessel wall destruction in a humanized mouse model.\",\n      \"method\": \"Patient macrophage studies, humanized mouse model of GCA, anti-IL-9 antibody treatment, recombinant IL-9 administration, flow cytometry\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — humanized mouse model with functional intervention (anti-IL-9, rIL-9) plus patient tissue analysis, single lab\",\n      \"pmids\": [\"37075705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The TH-111 antibody (assigned to CD96 cluster) immunoprecipitated the TACTILE (CD96) antigen and found it associated with the transferrin receptor on leukemic cells; CD96 (TACTILE) was identified as a marker of T-cell ALL and a subset of immature AML.\",\n      \"method\": \"Immunoprecipitation, antibody-based immunophenotyping by flow cytometry\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunoprecipitation experiment showing association with transferrin receptor, minimal mechanistic follow-up\",\n      \"pmids\": [\"9845376\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD96 (TACTILE) is an immunoglobulin superfamily transmembrane receptor expressed on T cells and NK cells that binds CD155 (PVR/necl-5) via its first Ig domain and also interacts with nectin-1; it competes with the activating receptor CD226 for shared ligands and can function as either an inhibitory checkpoint (suppressing NK cell cytokine responses and Th9 inflammatory activity) or a co-stimulatory receptor (enhancing CD8+ T cell activation via MEK-ERK signaling) depending on cell context; within tumor cells it drives chemoresistance via a CD155-CD96-Src-Stat3-Opa1 pathway promoting mitochondrial fatty acid β-oxidation; CD96 mutations that reduce CD155 binding cause the C (Opitz trigonocephaly) syndrome, and loss of CD96 surface checkpoint function contributes to autoimmune vasculitis by permitting pathogenic Th9 expansion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD96 (TACTILE) is an immunoglobulin-superfamily transmembrane receptor on T cells and NK cells that engages nectin-family adhesion ligands to tune immune effector responses [#0, #3]. It binds the poliovirus receptor CD155 (necl-5) through its outermost V-like first Ig domain, with the crystal structure of the CD96 D1:CD155 complex revealing a conserved lock-and-key interface whose CD155-versus-nectin-2 specificity is set by an 'ancillary key' motif [#2, #6]; CD96 also binds nectin-1 at a lower affinity via the canonical nectin V-domain interface [#7]. This adhesive engagement was first defined functionally by CD96-dependent NK adhesion to CD155-bearing targets and acquisition of CD155 from those cells [#0]. CD96 competes with the activating receptor CD226 (DNAM-1) for CD155, and through this competition acts as a negative regulator of NK-cell cytokine output, with Cd96-deficient mice showing hyperinflammatory LPS responses and resistance to experimental metastasis [#3, #11]. The receptor's output is context-dependent: it serves as an inhibitory checkpoint on CD8+ T cells, where blockade enhances CD8-dependent tumor control and synergizes with anti-PD-1 [#8], yet crosslinking CD96 also drives co-stimulatory CD8+ T-cell activation, cytokine production, and proliferation through MEK-ERK signaling [#9]. In Th9 cells, CD96 expression restrains IL-9 production and inflammatory expansion, and a defective CD155-CD96 checkpoint—macrophages retaining CD155 in the ER—permits expansion of pathogenic CD96+ IL-9-producing T cells in giant cell arteritis [#10, #13]. Beyond immune cells, tumor-intrinsic CD96 drives chemoresistance via a CD155-CD96-Src-Stat3-Opa1 axis promoting mitochondrial fatty acid β-oxidation [#12], and CD96 marks AML leukemic stem cells with engraftment activity [#5]. A T280M missense mutation in the third Ig domain that reduces CD155 binding causes a form of C (Opitz trigonocephaly) syndrome, linking CD96-mediated adhesion to development [#2, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Before any ligand or function was known, CD96/TACTILE needed to be defined as a discrete leukocyte antigen and clinical marker, establishing the protein and its disease associations.\",\n      \"evidence\": \"Immunoprecipitation and antibody immunophenotyping on leukemic cells\",\n      \"pmids\": [\"9845376\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single immunoprecipitation with minimal mechanistic follow-up\", \"Functional significance of transferrin receptor association not established\", \"No ligand identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The central question of what CD96 does was first answered by identifying CD155/PVR as its ligand and showing the interaction supports NK adhesion and cytotoxicity, establishing CD96 as a functional adhesion receptor.\",\n      \"evidence\": \"Cell adhesion, cytotoxicity, and ligand-acquisition assays with NK cells and PVR+ targets\",\n      \"pmids\": [\"15034010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which Ig domain mediates binding\", \"Signaling output downstream of CD96 unknown\", \"Inhibitory vs activating role not distinguished\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Ligand specificity was broadened and the receptor framed in a developmental context by showing nectin-1 is a second adhesion ligand and that CD96 mutations cause C syndrome.\",\n      \"evidence\": \"Antibody-blocking adhesion assays in mouse plus translocation mapping and patient mutation functional assays\",\n      \"pmids\": [\"17971293\", \"17847009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking adhesion defect to trigonocephaly developmental phenotype unresolved\", \"Single-lab functional assays for patient mutation\", \"Relative contribution of CD155 vs nectin-1 in development not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The molecular basis of binding was localized to the V-like D1 domain and the disease mutation explained, showing the C-syndrome T280M mutation in D3 allosterically reduces CD155 binding of both splice variants.\",\n      \"evidence\": \"Chimeric human/murine receptor binding assays, splice variant characterization, mutagenesis of patient mutation\",\n      \"pmids\": [\"19056733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution interface not yet defined\", \"Mechanism of allosteric modulation by downstream domains not structurally explained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The functional valence was resolved in NK cells by demonstrating CD96 competes with activating CD226 for CD155 and acts as an inhibitory checkpoint, with knockout mice showing enhanced anti-metastatic immunity.\",\n      \"evidence\": \"Cd96 knockout mice, competitive CD155 binding assays, LPS and experimental metastasis models\",\n      \"pmids\": [\"24658051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling motifs mediating inhibition not mapped\", \"Whether the same logic applies to T cells unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The receptor's role was extended to adaptive immunity and the ligand-dependency of therapeutic blockade dissected, showing CD96 restrains Th9 IL-9 inflammatory potential and that anti-CD96 anti-metastatic activity requires CD155 and CD226.\",\n      \"evidence\": \"Adoptive transfer of CD96low/high Th9 cells into Rag1-/- mice, antibody domain-mapping, CD155-KO and CD226-KO metastasis models\",\n      \"pmids\": [\"29531070\", \"29721390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway connecting CD96 to IL-9 suppression unknown\", \"How CD226 is required for CD96-blockade efficacy mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The CD96:CD155 interface was solved at atomic resolution, defining a lock-and-key binding mode and an 'ancillary key' motif conferring CD155 over nectin-2 specificity.\",\n      \"evidence\": \"X-ray crystallography of CD96-D1:CD155 complex with mutagenesis validation\",\n      \"pmids\": [\"30528596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length receptor or signaling-competent complex not determined\", \"Does not address nectin-1 binding geometry\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CD96's bifunctional immune role and its second ligand interface were clarified, establishing CD96 as a CD8+ T-cell checkpoint whose blockade boosts tumor control and defining the nectin-1 binding site.\",\n      \"evidence\": \"Cd96-deficient tumor models with CD8 depletion and anti-PD-1 combination; in vitro nectin-1 binding/affinity and NK cytotoxicity assays\",\n      \"pmids\": [\"30894377\", \"30759143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of CD96-nectin-1 binding in vivo unclear\", \"Reciprocal validation of nectin-1 interaction limited to single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An apparent paradox was addressed by showing CD96 can also co-stimulate CD8+ T cells through MEK-ERK signaling, revealing context-dependent dual activity rather than purely inhibitory function.\",\n      \"evidence\": \"CD96 crosslinking on human and mouse CD8+ T cells, MEK-ERK inhibition, genetic KO and in vivo models\",\n      \"pmids\": [\"32043568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines inhibitory vs co-stimulatory outcome not defined\", \"Direct link between ligand engagement and MEK-ERK activation not structurally explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A tumor-cell-intrinsic role was uncovered, showing CD96 drives chemoresistance through a CD155-CD96-Src-Stat3-Opa1 axis promoting mitochondrial fatty acid β-oxidation.\",\n      \"evidence\": \"CD96 inhibition in cell lines and PDX models, pathway analysis, β-oxidation assays, in vivo chemotherapy response\",\n      \"pmids\": [\"36581470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway dissection\", \"How a surface receptor couples to mitochondrial metabolism mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The checkpoint logic was placed in human autoimmune disease, showing defective CD155 surface display creates a failed CD155-CD96 checkpoint that expands pathogenic IL-9-producing CD96+ T cells in giant cell arteritis.\",\n      \"evidence\": \"Patient macrophage studies, humanized GCA mouse model with anti-IL-9 and recombinant IL-9 interventions\",\n      \"pmids\": [\"37075705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why macrophages retain CD155 in the ER not explained\", \"Single-lab humanized model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular switch governing whether CD96 acts as an inhibitory checkpoint or co-stimulatory receptor, and the intracellular signaling motifs coupling ligand engagement to each outcome, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined cytoplasmic signaling motif map\", \"Determinants of context-dependent valence unknown\", \"Integration of CD96/CD226 competition with downstream signaling unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 8, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD155\", \"CD226\", \"NECTIN1\", \"TFRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}